In general, the biosynthesis of all mitomycins proceeds via combination of 3-amino-5-hydroxybenzoic acid (AHBA),
D-glucosamine, and
carbamoyl phosphate, to form the mitosane core, followed by specific tailoring steps. The key intermediate, AHBA, is a common precursor to other anticancer drugs, such as
rifamycin and ansamycin. Specifically, the biosynthesis begins with the addition of
phosphoenolpyruvate (PEP) to
erythrose-4-phosphate (E4P) with a yet undiscovered enzyme, which is then ammoniated to give 4-amino-3-deoxy-D-arabino heptulosonic acid-7-phosphate (aminoDHAP). Next,
DHQ synthase catalyzes a ring closure to give 4-amino3-dehydroquinate (aminoDHQ), which then undergoes a double oxidation via aminoDHQ dehydratase to give 4-amino-dehydroshikimate (aminoDHS). The key intermediate, 3-amino-5-hydroxybenzoic acid (AHBA), is made via aromatization by AHBA synthase. Synthesis of the key intermediate, 3-amino-5-hydroxy-benzoic acid. The mitosane core is synthesized as shown below via condensation of AHBA and
D-glucosamine, although no specific enzyme has been characterized that mediates this transformation. Once this condensation has occurred, the mitosane core is tailored by a variety of enzymes. Both the sequence and the identity of these steps are yet to be determined. • Complete reduction of C-6 – Likely via F420-dependent tetrahydromethanopterin (H4MPT) reductase and H4MPT:CoM methyltransferase • Hydroxylation of C-5, C-7 (followed by transamination), and C-9a. – Likely via cytochrome P450 monooxygenase or benzoate hydroxylase • O-Methylation at C-9a – Likely via SAM dependent methyltransferase • Oxidation at C-5 and C8 – Unknown • Intramolecular amination to form aziridine – Unknown • Carbamoylation at C-10 – Carbamoyl transferase, with carbamoyl phosphate (C4P) being derived from L-citrulline or L-arginine ==Biological effects==